SUMMARY ? PROJECT 2: PGC-1 SIGNALING AND MITOCHONDRIAL STRESS IN MELANOMA During the process of melanoma formation, progression, and treatment, dramatic changes in metabolism occur and are required for the evolving energetic and biosynthetic needs of rapidly proliferating cells. Mitochondria serve as a central integration point for this metabolic re-programming; regulating ATP synthetic capacity, redox signaling, and biosynthetic capability. Preliminary data presented in this P01 application demonstrate a dynamic feedback circuit in specific melanoma subsets involving ATF4, MITF, and PGC-1? transcription factors. The ATF4?MITF?PGC-1? axis is responsive to ER stress, nutrient deprivation, and melanoma driver mutations, and regulates responses to targeted therapies, ROS stress, and metabolic stress. This Project is focused on the role of the PGC-1 family of transcription coregulators, PGC-1?, PGC-1?, and PRC, in these processes. Recent evidence indicates that PGC-1?, a master regulator of mitochondrial biogenesis and function, is upregulated in a subset of melanomas together with MITF. Elevated PGC-1? expression correlates with increased mitochondrial content and oxygen consumption rates. Interestingly, inhibition of BRAF in this subset of melanomas results in further increase in mitochondrial content, oxygen consumption and induces sensitivity to mitochondrial respiratory inhibitors. The interplay between the ER stress/unfolded protein response and PGC-1?/mitochondria will be characterized in Project 1. Mitochondria and PGC-1? also integrate signals related to glutamine metabolism, a focus of Project 3. We hypothesize that mitochondrial functional capacity, as determined by the activity of PGC-1 factors, coordinates cellular stress responses and can be used to define susceptibility to mitochondrial-targeted agents for clinical intervention. To characterize the role of PGC-1?, PGC-1?, PRC and mitochondrial function in melanoma, we will (1) determine the functional role of the MITF/PGC-1?/ERR? pathway in the metabolic regulation of melanoma formation and treatment response and (2) evaluate the role of PGC-1? and PRC in melanoma metabolic regulation, stress responses, and sensitivity to therapeutic intervention. Our studies will be closely integrated with Projects 1 and 3, and will require the use of Cores B and C.